EFFECT OF POLYMER RATIO AND EXCIPIENTS ON METOPROLOL TARTRATE RELEASE FROM CHITOSAN – SODIUM ALGINATE POLYMERIC IMPLANTSHTML Full Text
EFFECT OF POLYMER RATIO AND EXCIPIENTS ON METOPROLOL TARTRATE RELEASE FROM CHITOSAN - SODIUM ALGINATE POLYMERIC IMPLANTS
Rifat Ara Islam, Afsana Tabassum, Amer Khorshed Alam and Swarnali Islam*
Department of Pharmacy, University of Asia Pacific, 74/A Green Road, Dhaka - 1215, Bangladesh.
ABSTRACT: Natural biodegradable chitosan-sodium alginate polymer combination is a promising candidate for preparing drug-loaded implants because of the availability and inexpensiveness of the polymers over the semi synthetic biodegradable ones. The main objective of this research was to prepare and evaluate a biodegradable implantable system of the drug metoprolol tartrate because it plays an important role in the treatment of high blood pressure, strokes, heart attacks and angina. 70:30 and 80:20 chitosan - sodium alginate combination implants of metoprolol tartrate with 15 and 30 minutes exposure time to glutaraldehyde for hardening were prepared. It was observed that loading efficiency and drug release could be influenced by varying polymer ratios, exposure times to glutaraldehyde and excipients. The implant formulated with 25 mg drug load in 70:30 chitosan - sodium alginate ratio with 15 minutes exposure produced the maximum sustained release for 15 days. Therefore, this formulation was chosen for preparing implants containing different excipients and the implants were evaluated for loading efficiency and in-vitro drug release. Morphological characteristics of the implants were analyzed using SEM. The release mechanism was explored and explained with zero order, first order, higuchi and korsmeyer-peppas models. Implants with excipients were found to follow first order model in most cases. also good co-relations were obtained with higuchi model. According to these models, the drug release from the implants was diffusion controlled, where the drug leaving the matrix through pores and channels formed by entry of dissolution medium.
Biodegradable Polymeric, Implant, Chitosan, Sodium, Alginate, Glutaraldehyde, Metoprolol Tartrate
INTRODUCTION: The concept of sustaining or prolonging the release of biologically active agents for extended periods of time has been well appreciated and rationalized for decades to overwhelm the drawbacks of fluctuating drug level associated with conventional dosage forms 1, 2. Polymeric drug delivery system provides an attractive capability of releasing the drug from formulations in a synchronized manner and constant rate over extended periods 3.
Patients suffering from some acute and chronic disease conditions often get benefits from such long-term drug delivery systems as they maintain the drug concentration in plasma above the minimum effective concentration and below the minimum toxic level for prolonged period of time 4. Biodegradable polymers recently have gained much popularity in the development of several novel drug delivery systems 5. As these polymers have either hydrolytically or proteolytically labile bond in their backbones, they are ruptured into biologically suitable molecules that are assimilated and discarded from the body through normal routes 6. However, biodegradable materials do produce degradation byproducts that must be tolerated with little or no adverse reactions within the biological environment 7.
Thus biodegradable polymeric implant alleviates the need for surgical removal of the implant after the conclusion of therapy and increases patient acceptance and compliance 8. We attempted formulating Chitosan - Sodium Alginate polymeric implant so that the drug could release over a prolonged period of time. Chitosan, a cationic natural biopolymer, produced by alkaline N-deacetylation of chitin, has attracted much attention over the past few years mainly because of its biodegradable, biocompatible, renewable, sustainable, non-toxic, film forming and antimicrobial properties 9, 10. Chitosan and its derivatives can be used in implantable drug delivery systems as high molecular weight Chitosan is more viscous and delays the release of the active ingredient, prolongs the duration of drug activity, improves therapeutic efficiency as well as reduces the side effects 11.
Sodium Alginate, an anionic biodegradable polysaccharide, consists chiefly of the sodium salt of alginic acid, has received attention as a vehicle for controlled drug delivery due to its hydrogel-forming properties. When it comes in contact with aqueous media, forms viscous solutions and gels and thus prolongs the release of many drugs. Due to this property, Sodium Alginate is now widely used as a carrier in hydrophilic matrix controlled and sustained release dosage forms in many pharmaceutical industries 12.
The aim of the research was to explore the scope of sustaining the release of Metoprolol Tartrate, which is used in treatment of several diseases of the cardiovascular system, especially in hypertension, angina pectoris, cardiac arrhythmias and myocardial infarction 13, using Chitosan-Sodium Alginate biodegradable implants. Metoprolol Tartrate, available as immediate release tablets, is subjected to first-pass metabolism which reduces its systemic availability by about 50%. Therefore, entrapping it in sustained release implant formulations will improve its availability by avoiding first-pass metabolism and also patient compliance by reducing dosing frequency 14, 15.
MATERIALS AND METHODS:
Materials: The active ingredient Metoprolol Tartrate was provided by Incepta Pharmaceuticals Ltd., Dhaka, Bangladesh. Other chemicals were of analytical grade. The research was performed in Department of Pharmacy, University of Asia Pacific, Dhaka, Bangladesh from May 2016 to October, 2016.
Preparation of Implants: Biodegradable implants of Metoprolol Tartrate were prepared by the use of two biodegradable polymers, Chitosan and Sodium Alginate. Implants were prepared using 25 mg drug with 2 different polymer ratios (70:30 and 80:20) as well as 25 mg drug load with 70:30 polymer ratio containing different excipients. 100 ml of 1% acetic acid solution was used to dissolve 4.167 g of Chitosan. 100 ml of distilled water was taken to dissolve 4.167 g of Sodium Alginate. The solutions were stirred until no large chunks remained and then blended until homogenous 16, 17. Chitosan and Sodium Alginate solutions were then taken according to the respective ratios (70:30 and 80:20). Metoprolol Tartrate was then dispersed to the Chitosan and Sodium Alginate solutions. Excipient was added along with drug when implants were prepared using different excipients. After being mixed with ultrasonic, the mixture was poured into petridish. Then it was allowed to set by placing in a refrigerator at - 32 °C for 1 day. After 1 day, implants were cut into 1 cm width and 1 cm length square shape by NT cutter.
Hardening of Implants: Chemical cross linking can effectively guard the physicochemical stability of Chitosan applications since the gelation is irreversible. The higher stability of such modified Chitosan is based on the covalent bonds, but also other interactions (hydrogen or hydrophobic bonds) cannot be excluded. The most common chemical crosslinkers of Chitosan are dialdehydes (such as glutaraldehyde or glyoxal) and genipin 18. The prepared implants were placed into a cross-linking solution of glutaraldehyde for 15 minutes and 30 minutes for hardening. Then they were washed with methanol and distilled water, respectively. After hardening they were placed in aseptic cabinet for air drying for few minutes. Table 1 and 2 show different formulations that had been prepared.
Characterization of Implants:
Photographic Implant: Photographs of drug loaded implants were taken using SONY Cyber-shot, 14.1 Mega Pixel Camera. Fig. 1 shows photo-graphic images of Metoprolol Tartrate implants.
TABLE 1: FORMULATION CHART OF IMPLANTS WITH DIFFERENT POLYMER RATIOS AND EXPOSURE TIMES
|Name of Formulation||Polymer Ratio||Drug Loading||Glutaraldehyde Exposure|
|F1||70:30||25 mg||15 minutes|
|F2||70:30||25 mg||30 minutes|
|F3||80:20||25 mg||15 minutes|
|F4||80:20||25 mg||30 minutes|
TABLE 2: FORMULATION CHART OF IMPLANTS WITH 15 MINUTES EXPOSURE TIME CONTAINING DIFFERENT EXCIPIENTS
|Name of Formulation||Polymer Ratio||Drug Loading||Excipient Loading||Excipients|
|F5||70:30||25 mg||25 mg||Glyceryl Monostearate|
|F6||70:30||25 mg||25 mg||Cetyl Alcohol|
|F7||70:30||25 mg||25 mg||Guar Gum|
|F8||70:30||25 mg||25 mg||Stearic Acid|
|F9||70:30||25 mg||25 mg||Sesame Oil|
|F10||70:30||25 mg||25 mg||Glyceryl Behenate|
|F11||70:30||25 mg||25 mg||Kollidon SR|
|F12||70:30||25 mg||25 mg||Eudragit RS-100|
FIG. 1: PHOTOGRAPHIC IMAGES OF METOPROLOL TARTRATE IMPLANTS
Scanning Electron Microscope (SEM): Prepared implants were analyzed for their surface morphology by scanning electron microscope. The implants were initially spread on a carbon tape glued to an aluminium stub and coated with Au using a sputter coater under vacuum in a closed chamber. The Au layer was coated to make the implant surface conductive to electrons in the SEM. The implants were then observed under SEM in varying magnifications and micrographs were recorded. Scanning electron microscope (SEM) was used to observe interior morphology at cross section of hot-melt extrudates. Hot-melt extrudates were cut into approximately 3 - 5 mm pieces.
In-vitro Dissolution Studies: The in-vitro release of Metoprolol Tartrate from implants was carried out in static conditions at 37 °C. The weighed implants (at least 3 implants) from each formulation and exposure time were kept in rubber capped glass vessels containing 100 ml of Phosphate Buffer, pH 7.4. 3 ml of the release medium was collected at predetermined time intervals and replaced with 3 ml of fresh buffer to maintain the sink condition 19, 20. The withdrawn samples were then analyzed for determining the percentage of release of drugs by UV spectrophotometer at 273.5 nm (𝛌max of Metoprolol Tartrate in Phosphate Buffer, pH 7.4), after subsequent dilution of the samples. All data were used in statistical analysis for the determination of mean, standard deviation and release kinetics.
Statistical Analysis: Results were expressed as mean ± S.D. Statistical analysis was performed by linear regression analysis. Coefficients of determination (R2) were utilized for comparison. In-vitro release studies were performed under the same conditions for each implant system. The means and standard deviations were calculated at each time interval. The means were graphed for each release profile with the standard deviations included as error bars. Linear regression was performed on cumulative drug release as a function of time and also on fitted curves to different kinetic models.
Determination of Drug Content (Loading Dose): The amount of drug that was actually loaded in implants during fabrication process was determined by spectrophotometric analysis. For determining the drug content of Metoprolol Tartrate loaded implants, first the implants were weighed and then crushed in a mortar and pestle. Then they were dissolved in 2 ml acetic acid by vigorous ultrasonication. Then 2 ml of acetronitrile, 4 ml hot buffer and 2 ml acetic acid were added for precipitating the polymer and extracting the drug in solvent. The total volume of acetic acid, acetonitrile and Phosphate Buffer (pH 7.4) ratio was 40:20:40. Then it was centrifuged at 4000 RPM for 30 minutes to separate the solid material. Clear supernatant was withdrawn and it was analyzed at 273.5 nm (λmax of Metoprolol Tartrate) in UV spectrophotometer. The percentage of loading efficiency (% LE) of implants was determined with the formula:
% LE = (LD/AD) × 100
Where; LD is the amount of loaded drug in the implant and AD is the amount of added drug in the formulation 21.
RESULTS AND DISCUSSION:
Scanning Electron Microscope (SEM): Fig. 2 and 3 show SEM micrograph of Chitosan-Sodium Alginate polymeric implant surface containing Metoprolol Tartrate before drug release and after drug release.
FIG. 2: SEM MICROGRAPH OF METOPROLOL TARTRATE POLYMERIC IMPLANT SURFACE BEFORE DRUG RELEASE (100 AND 500 TIMES MAGNIFIED)
FIG. 3: SEM MICROGRAPH OF METOPROLOL TARTRATE POLYMERIC IMPLANT SURFACE AFTER DRUG RELEASE (100 AND 500 TIMES MAGNIFIED)
Fig. 2 and 3 display SEM micrograph of Metoprolol Tartrate Chitosan - Sodium Alginate polymeric implant surface before and after drug release (100 and 500 times magnified). Before drug release the implant surface is nonporous, smooth and the surface integrity is also found to be good.
But after drug release, the micrographs show the surface to be more porous and rough. It indicates that very low amount of drug was remaining after drug release which also complies with the findings of drug release studies.
Effect of Excipients on Loading Efficiency of Chitosan-Sodium Alginate Polymeric Implants: The changes in the loading efficiency of the implants were probably caused by the respective excipients. The data for different excipients with 25 mg load of Metoprolol Tartrate are presented in the Table 3.
TABLE 3: EFFECT OF EXCIPIENTS ON LOADING EFFICIENCY OF CHITOSAN-SODIUM ALGINATE POLYMERIC IMPLANTS OF METOPROLOL TARTRATE
|Formulation||Excipient||Loading Efficiency (%)|
|F5||Glyceryl Monostearate||76.64 (maximum)|
|F9||Sesame Oil||57.43 (minimum)|
The highest loading efficiency was found with Glyceryl Monostearate (76.6%) and the lowest with Sesame Oil (57.4%). The loading efficiency was found to decrease in the following sequence:
Glyceryl Monostearate > Cetyl Alcohol > Glyceryl Behenate > Kollidon SR > Guar Gum > Stearic
Acid > No Excipient > Eudragit RS-100 > Sesame Oil.
Effect of inclusion of excipients on loading efficiency (%) of Metoprolol Tartrate in Chitosan-Sodium Alginate polymeric implants is displayed in Fig. 4.
Drug Release Profile of Implants Based on Varying Chitosan-Sodium Alginate Polymer Ratios and Different Exposure Times: Drug release profile of implants in combination of 70:30 and 80:20 Chitosan-Sodium Alginate polymeric ratios with 15 minutes and 30 minutes exposure time (F1, F2, F3 and F4) is shown in Fig. 5. From Fig. 5, it can be said that time taken for F1, F2, F3 and F4 formulations to release nearly 100% of the drug was 15 days, 10 days, 10 days and 8 days respectively. As F1 formulation released the drug for more days compared to other formulations, this formulation was chosen for further development of implants with incorporation of different excipients.
FIG. 4: EFFECT OF INCLUSION OF EXCIPIENTS ON LOADING EFFICIENCY (%) OF METOPROLOL TARTRATE CHITOSAN - SODIUM ALGINATE POLYMERIC IMPLANTS
FIG. 5: DRUG RELEASE PROFILE OF 70:30 AND 80:20 CHITOSAN-SODIUM ALGINATE POLYMERIC IMPLANTS WITH 15 AND 30 MINUTES EXPOSURE TIMES (F1, F2, F3 AND F4)
Effect of Excipients on Drug Release from 70:30 Chitosan-Sodium Alginate Polymeric implants with 15 minutes Exposure Time: Excipients have various effects on drug release profile. The rate and extent of drug release from implants can be controlled by the use of excipients in the formulation. These agents can act as rate modifier by increasing or retarding the rate of release depending upon the nature of the agent. They probably extent their effects by influencing the way of formulation formed and therefore on the release characteristics of the sustained release implants 22. Comparison of drug release profile of implants containing different excipients with F1 (70:30 polymer ratio with 15 minutes exposure time) is graphically represented in Fig. 6 and 7.
From Fig. 6 and 7, it is observed that among all excipients, F5 (Glyceryl Monostearate) showed the maximum sustain release effect and F12 (Eudragit RS-100) showed the minimum sustain release effect when compared to F1 (No Excipient). Glyceryl Monostearate has a HLB value of 3.8 which indicates its hydrophobic nature and it is practically insoluble in water. It is used as a matrix ingredient for a biodegradable, implantable, controlled release dosage form 23. Eudragit RS-100 is practically insoluble in water and is used in delayed and sustained drug release 24. But it failed to give the expected sustained release effect which should be more than 15 days. So, further investigation is needed in this regard. Time taken for all formulations containing excipients to release nearly 100% of the drug is displayed in Table 4.
FIG. 6: COMPARISON OF METOPROLOL TARTRATE RELEASE PROFILE OF FORMULATIONS F1, F5, F6, F7 AND F8
FIG. 7: COMPARISON OF METOPROLOL TARTRATE RELEASE PROFILE OF FORMULATIONS F1, F9, F10, F11 AND F12
TABLE 4: TIME TAKEN FOR ALL FORMULATIONS CONTAINING EXCIPIENTS TO RELEASE NEARLY 100% OF THE DRUG
|Formulation||Calculated time (Days) for drug release|
|F1 (No Excipient)||15|
|F5 (Glyceryl Monostearate)||30|
|F6 (Cetyl Alcohol)||20|
|F7 (Guar Gum)||20|
|F8 (Stearic Acid)||20|
|F9 (Sesame Oil)||15|
|F10 (Glyceryl Behenate)||25|
|F11 (Kollidon SR)||15|
|F12 (Eudragit RS-100)||10|
Kinetics of Drug Release Study: The release profile and kinetics of drug release are important because they correlate the in-vitro and in-vivo drug responses by comparing result of dissolution profile and pharmacokinetic patterns 25. The kinetics of Metoprolol Tartrate from 70:30 Chitosan-Sodium Alginate polymeric ratio containing different excipients with 15 min exposure time were determined by finding the best fit of the release data to Higuchi, Korsmeyer-peppas, Zero order and First order plots.
TABLE 5: FITTING COMPARISON OF EQUATION OF KINETIC MODELS
|Formulations||Higuchi||Korsmeyer-peppas||Zero order||First order|
FIG. 8: HIGUCHI PLOT OF METOPROLOL TARTRATE RELEASE FROM FORMULATIONS F1, F7, F11 AND F12
FIG. 9: FIRST ORDER PLOT OF METOPROLOL TARTRATE RELEASE FROM FORMULATIONS F5, F6, F8, F9 AND F10
From Table 5, it can be said that implants with excipients were found to follow First order model in most cases. Also good co-relations were obtained with Higuchi model which are shown in Fig. 8 and 9.
Higuchi model describes drug release as a square root time dependent diffusion process based on Fick’s law 26 and First order model describes drug release from the system where release rate is concentration dependent 27. According to these models, the drug release from the implants was diffusion controlled, where the drug leaving the matrix through pores and channels formed by entry of dissolution medium.
CONCLUSION: Metoprolol Tartrate, a cardio selective beta-blocker, used in management of high blood pressure, irregular heart rhythm, strokes, heart attacks and angina pectoris, is available as immediate release dosage forms which require frequent dose administration. Dosage forms that release the drug over a prolonged length of time can be prepared by incorporating drug into biodegradable polymeric implants. Biodegradable polymeric implants will improve the patience compliance by reducing the dosing frequency and there will be no need of surgical removal of the implants as the polymers will be degraded and cleared by the body.
The effects of different polymer ratios and excipients were studied on loading efficiency and drug release profile of Chitosan-Sodium Alginate polymeric implants of Metoprolol Tartrate. The implants exhibited high drug loading efficiency and long term drug release under in-vitro conditions with most of the excipients. Thus biodegradable polymers offer a novel approach for sustained release drug delivery systems that are simple and convenient to the patients.
ACKNOWLEDGEMENT: The authors are thankful to University of Asia Pacific for providing the necessary lab facilities for conducting this research and also thankful to Incepta Pharmaceuticals Ltd., Bangladesh for providing support with the active ingredient.
CONFLICT OF INTEREST: The authors declare no conflict of interest.
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How to cite this article:
Islam RA, Tabassum A, Alam AK and Islam S: Effect of polymer ratio and excipients on metoprolol tartrate release from chitosan-sodium alginate polymeric implants. Int J Pharm Sci Res 2018; 9(6): 2293-00. doi: 10.13040/IJPSR.0975-8232.9(6).2293-00.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
R. A. Islam, A.Tabassum, A. K. Alam and S. Islam *
Department of Pharmacy, University of Asia Pacific, Dhaka, Bangladesh.
28 August, 2017
30 November, 2017
25 December, 2017
01 June, 2018